Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy

TY - JOUR

T1 - Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy

AU - De Stasi, Angela Michela

AU - Farisello, Pasqualina

AU - Marcon, Iacopo

AU - Cavallari, Stefano

AU - Forli, Angelo

AU - Vecchia, Dania

AU - Losi, Gabriele

AU - Mantegazza, Massimo

AU - Panzeri, Stefano

AU - Carmignoto, Giorgio

AU - Bacci, Alberto

AU - Fellin, Tommaso

N1 - © The Author 2016. Published by Oxford University Press.

PY - 2016/4

Y1 - 2016/4

N2 - Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a(-/+) mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a(-/+) mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a(-/+) during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a(-/+) mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a(-/+) compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a(-/+) mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI.

AB - Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a(-/+) mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a(-/+) mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a(-/+) during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a(-/+) mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a(-/+) compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a(-/+) mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI.

KW - Action Potentials

KW - Animals

KW - Brain Waves

KW - Cerebral Cortex/physiopathology

KW - Disease Models, Animal

KW - Female

KW - Interneurons/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - NAV1.1 Voltage-Gated Sodium Channel/genetics

KW - Neural Pathways/physiopathology

KW - Opsoclonus-Myoclonus Syndrome/genetics

KW - Parvalbumins/metabolism

KW - Somatostatin/metabolism

KW - Synaptic Potentials

U2 - 10.1093/cercor/bhw002

DO - 10.1093/cercor/bhw002

M3 - SCORING: Journal article

C2 - 26819275

VL - 26

SP - 1778

EP - 1794

JO - CEREB CORTEX

JF - CEREB CORTEX

SN - 1047-3211

IS - 4

ER -